25 August 2010

Oncogenes and anti-oncogenes: who's who?

Animal cells are constantly trying to be rebornNadezhda Markina, Infox.ru
Scientists have found out which genes and proteins play in the cell for and against a malignant tumor and who has what role.

The mechanism will help to find new drugs and biomarkers of cancer.

The development of malignant tumors in the body is opposed by the anti-cancer protection system. Its main participant, the p53 gene, has been known for quite a long time, but until now scientists did not understand what makes it activate and act.  

Scientists from the Beth Israel Deaconess Medical Center (Beth Israel Deaconess Medical Center) – the basic clinic of the Harvard Medical School in Boston – under the leadership of Wei Wenyi (Wenyi Wei) on cell cultures and mice deciphered the anti-cancer mechanism of the interaction of genes and proteins. The results of their work are published in the journal Cancer Cell (Hiroyuki Inuzuka et al., Phosphorylation by Casein Kinase I Promotes the Turnover of the Mdm2 Oncoprotein via the SCF β-TRCP Ubiquitin Ligase).

Protein p53 is a product of p53 gene activity. When damage appears in the DNA of a cell, the protein slows down the mechanism of cell division in order to allow repair proteins to repair malfunctions. If the damage is so great that it cannot be repaired, he also gives the command to destroy the cell by apoptosis.

Apoptosis is a programmed form of cell death, manifested in a decrease in its size, condensation and fragmentation of chromatin, compaction of the outer and cytoplasmic membranes without the release of the contents of the cell into the environment.
Mutations of the p53 gene (and, accordingly, a protein that is not able to protect the cell from malignant degeneration) are found in about 50% of cancerous tumors.

The fight of proteins is not for life, but for deathBiologists have found out that p53 is in constant struggle with another protein – MDM2.

"They, like yin and yang, carry opposite beginnings, and the fate of the cell depends on the balance between them," explains Wei Wenyi. – When DNA is damaged in a cell, MDM2 is eliminated and allows p53 to stop cell division for repair. When MDM2 reappears, it blocks p53, and the normal life cycle of the cell continues." It is clear that the corresponding genes are behind these proteins. MDM2 is a product of the MDM2 oncogene, which is constantly working in the cell. With normal activity, it does not cause cancer, but an excess of MDM2 protein contributes to the malignant transformation of the cell.

Oncogene is a gene encoding a protein that, in case of a violation of regulation, can cause the formation of a cancerous tumor. Mutations that cause the activation of oncogenes increase the chance that the cell will turn into a cancerous one.

The key element of this system that had to be found is what causes the MDM2 protein to give up its position and give way to p53. Studies have shown that MDM2 degrades under the action of two enzymes. First, casein kinase I (CKI) is taken for it, which is immediately activated when DNA is damaged. But its role is only in the phosphorylation of the MDM2 protein. The addition of phosphate groups to a protein molecule can both give it functional activity and take it away. In this case, the latter happens.

Molecular rheostatAs scientists have found out, the protein does not just turn off.

"It's not like a switch, but a rheostat – a smooth power regulator to a complete stop," says Wei Wenyi. The work of the protein is gradually reduced by the addition of more and more phosphate groups.

In phosphorylated form, MDM2 becomes available to the action of another enzyme – β-TRCP1. This enzyme puts a "black mark" on MDM2 – the ubiquitin protein molecule. It attaches to the amino groups of the protein and deprives it of functional activity. The final destruction of MDM2 is carried out by the proteasome 26S – a protein complex-destroyer.

Ubiquitin is a small protein that is attached by covalent bonds to the side amino groups of the target protein. Its attachment affects the intracellular localization and function of proteins.

In the future – new drugs and biomarkersKnowing all the participants in the process and their role, you can find ways to influence them.

It is known that in more than half of cancerous tumors, the p53 protein is too small for it to work effectively. So, it is necessary to suppress the activity of its competitor – MDM2 protein, scientists believe, and this can be achieved through casein kinase I. If, during genetic analysis, it turns out that some mutations weaken the work of CKI or beta-TRCP1 in cancer patients, specialists will have new cancer biomarkers at their disposal.

Portal "Eternal youth" http://vechnayamolodost.ru25.08.2010

Found a typo? Select it and press ctrl + enter Print version